Retracted: Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells

Abstract

Genistein is a phytoestrogen that has been reported to suppress the AKT signaling pathway in several malignancies. However, the molecular mechanism of genistein action is not known. We tested the hypothesis that genistein activates expression of several aberrantly silenced tumor suppressor genes (TSGs) that have unmethylated promoters such as PTEN, CYLD, p53 and FOXO3a. We report here that genistein activates TSGs through remodeling of the heterochromatic domains at promoters in prostate cancer cells by modulating histone H3-Lysine 9 (H3-K9) methylation and deacetylation. Genistein activation involved demethylation and acetylation of H3-K9 at the PTEN and the CYLD promoter, while acetylation of H3-K9 at the p53 and the FOXO3a promoter occurred through reduction of endogenous SIRT1 activity. There was a decrease of SIRT1 expression and accumulation of SIRT1 in the cytoplasm from the nucleus. Increased expression of these TSGs was also reciprocally related to attenuation of phosphorylated-AKT and NF-jB binding activity in prostate cancer cells. This is the first report describing a novel epigenetic pathway that activates TSGs by modulating either histone H3-Lysine 9 (H3-K9) methylation or deacetylation at gene promoters leading to inhibition of the AKT signaling pathway. These findings strengthen the understanding of how genistein may be chemoprotective in prostate cancer. ' 2008 Wiley-Liss, Inc.Key words: genistein; prostate cancer; tumor suppressor gene Genistein (4 0 ,5,7-trihydroxyflavone), a naturally occurring isoflavenoid abundant in soy products, has been identified as an inhibitor of protein tyrosine kinases, which play key roles in cell growth and apoptosis. 1,2 Genistein has been reported to have estrogenic properties and antineoplastic activity in multiple tumor types. 3 One mode by which hormonal agents work is by regulating gene activity by modulating epigenetic events such as histone acetylation and DNA methylation. 4,5 Genistein was also found to have epigenetic effects in the mouse prostate. 6 Taken together, these findings suggest that genistein's antitumor activity may be mediated by epigenetic-based pathways. On the other hand, genistein induces apoptosis and inhibits the activation of nuclear factor kappaB (NF-jB) pathway, which could be mediated via AKT (AKT8 virus oncogene cellular homolog) signaling, the most important survival pathway in cellular signaling. 7 However, the precise molecular mechanism has yet to be characterized.AKT is a serine/threonine protein kinase functioning downstream of phosphatidylinositol 3-kinase (PI3K) in response to mitogen or growth factor stimulation. High-levels of AKT activation have been associated with the development and metastasis of several cancers. 8 AKT activation not only directly inhibits apoptosis by multiple mechanisms involved in inhibiting the conformational change of Bax, BAD and caspase-9 but also modulates apoptosis indirectly by influencing the activities of several transcription factors, including fork head transcription factors (FOXO) and...

NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

“…SIRT1 interacts with and deacetylates FOXO3a, which increases or decreases expression of different sets of FOXO3a target gene in response to oxidative stress (Brunet et al, 2004;Motta et al, 2004). SIRT1 can bind to FOXO3a promoter and presumably repress its transcription in PC3 and LNCaP cells (Kikuno et al, 2008). However, we found that SIRT1 knockdown did not affect FOXO3a protein expression (Figure 8c).…”

Epigenetic deregulation of miR-29a and miR-1256 by isoflavone contributes to the inhibition of prostate cancer cell growth and invasion

“…20 TRIM68 could functionally interact to reverse the methylation status of several genes including BTG3, GSTP1, RASSF1A, EPH2, BRCA1, p16, RARβ and MGMT. [32][33][34][35] Studies have also shown the regulatory effects of isoflavone genistein on the methylation of miR-221/222 and miR-145 in PCa cells. 36,37 These findings suggest the demethylating function of isoflavone.…”

The Complexity of DNA Transcends Epigenetics

“…A most timely example relates to the p53 locus, important in the biochemical pathophysiology of cancer [21][22][23]. The rarity of cancer in elephants may well be related to their possession of 20 separate chromosome sites (doublestranded DNA providing 40 copies) of the gene responsible for coding this function [24].…”